Complexes that consist of vitamin D compounds or analogs thereof with a 5Z,7E,10(19)-triene system and methylated derivatives of beta-cyclodextrin

ABSTRACT

The invention relates to complexes that consist of vitamin D compounds or analogs thereof with a 5Z,7E,10(19)-triene system and methylated derivatives of β-cyclodextrin, in particular a complex that consists of (thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol and heptakis-(2,6-di-O-methyl)-β-cyclodextrin (DIMEB).

This application claims the benefit of the filing date of U.S.Provisional Application Ser. No. 60/673,360 filed Apr. 21, 2006 which isincorporated by reference herein.

The invention relates to complexes that consist of vitamin D compoundsor analogs thereof with a 5Z,7E,10(19)-triene system and methylatedderivatives of the β-cyclodextrin, in particular a complex that consistsof(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland heptakis-(2,6-di-O-methyl)-β-cyclodextrin (DIMEB).

The application is based on the following definitions of terms:

Analogs: Analogs are compounds of a natural substance that arestructurally related to a guide structure and that have, at leastqualitatively, the same physiological action as the guide structure.

Natural Substances: Natural substances are compounds that occurnaturally in plants, animals and/or humans and are isolated therefrom.

Vitamin D Compounds: Vitamin D compounds are a fat-soluble group ofnatural substances, derived from 7,8-didehydrosterols by photochemicalring opening and isomerization, with more or less pronouncedanti-rachitic action. The vitamin D compounds include, for example,

-   -   calciferols such as cholecalciferol (vitamin D₃, calciol),        ergocalciferol, (vitamin D₂, ercalciol) and    -   Vitamin D precursors such as 7-dehydrocholesterol        (7,8-didehydrocholesterol, tacalciol, provitamin D₃, procalciol,        procholecalciferol) and ergosterol (ertacalciol, provitamin D₂)        and    -   Vitamin D metabolites such as calcifediol        (25-hydroxycholecalciferol, 25-hydroxy vitamin D₃, calcidiol,        pro-hormone), calcitriol (1α,25-dihydroxycholecalciferol,        soltriol, 1α,25-dihydroxy-vitamin D₃) and        24R,25-dihydroxycholecalciferol (hydroxycalcidiol), ercalcidiol        (25-hydroxyergocalciferol), ercalcitriol        (1α,25-dihydroxyergocalciferol, 1α,25-dihydroxy-vitamin D₂),        1α-hydroxycholecalciferol        Vitamin D Analogs: The vitamin D analogs are molecules with a        5Z,7E,10(19)-triene system.        Ratio of Use: Ratio of use is the molar ratio of educts (vitamin        D compound or analogs thereof to cyclodextrin) in the complex        production.        Mean Molar Ratio: Refers to the number of moles of vitamin D or        vitamin D derivative to the number of moles of cyclodextrin        derivative in a sample of the complex with a purity of the        complex of at least 98% (relative to the weights).        Cyclodextrin: Cyclodextrin is used as a generic term for all        native and modified cyclodextrins.        Cyclodextrin Derivatives: Cyclodextrin derivatives are compounds        in which the glucopyranose units in each case can be substituted        in one or more of the positions 2-O, 3-O and/or 6-O. The        substitution can be partial or complete, symmetrical or        unsymmetrical, uniform at each glucopyranose unit or different.        Cyclodextrin derivatives are also named modified cyclodextrins        below. Cyclodextrin derivatives can have 6, 7 or 8 glucopyranose        units.        DIMEB: Heptakis-(2,6-di-O-methyl)-β-cyclodextrin.        TRIMEB: Permethylated β-cyclodextrin with 21 methyl groups as        substituents.        RAMEB: Statistically methylated β-cyclodextrin (randomly        methylated β-cyclodextrin, MW 1303).

DIMEB, TRIMEB and RAMEB are commercially available with degrees ofpurity of up to 98% and more.

Vitamin D compounds and analogs thereof are in some cases highlyeffective substances that are used in a low therapeutic dose. Thevitamin D compounds include calcitriols. As pure substances and informulations, these substances are sensitive to atmospheric oxygen,temperature and light.

Cyclodextrins consist of 6-, 7- or 8-membered cyclically-arrangedglucopyranose units, optionally derivatized, which are glycosidicallybound via the 1-O or 4-O position. These cyclic glucopyranoseoligosaccharides are referred to as α, β or γ-cyclodextrins (so-calledSchardinger cyclodextrins). Cyclodextrins are produced from starch by,e.g., enzymatic means (Szejtly, J., Cyclodextrin Technology, Davies, J.E., Ed; Kluwer Academic Press, Dordrecht, The Netherlands 1988).

It is known to use cyclodextrins in pharmaceutical compositions. Becauseof their circular structure, cyclodextrins have a hydrophilic exteriorand a hydrophobic inside pocket. By encasing in particular hydrophobicareas of the molecule, cyclodextrins can achieve a “molecularencapsulation” or “masking” of active ingredients that is used as, forexample, protective encasing of sensitive molecules in cosmetic andpharmaceutical formulations. As a result, improved solubilities ofsubstances and even reduced toxicities can be achieved.

Native and modified cyclodextrins are distinguished. Nativecyclodextrins are the α-, β- and γ-cyclodextrins that are accessible tothe enzyme glucotransferase from starch. The high and low-membered ringsdo not play any significant role in practice.

Depending on substitution and degree of substitution, the modifiedcyclodextrins have varying properties. By introducing polar groups,their water solubility is increased; the complexes are then also oftenbetter water-soluble. The bioavailability of less water-soluble activesubstances can thus be improved. By way of example, hydroxyalkylderivatives, such as, e.g., hydroxypropyl-β-cyclodextrin (HP-β-CD), canbe mentioned here.

Methylated cyclodextrins with a degree of methylation <2, which are usedfor the production of complexes, are described in U.S. Pat. No.6,602,860. In U.S. Pat. No. 4,727,064, O-alkyl-substituted cyclodextrinsare disclosed for complexing active ingredients.

The amorphous methyl cyclodextrin is commercially available under thecyclodextrins that are methyl-substituted in one place. The latter tendsonly slightly toward forming crystalline complexes. For the most part,amorphous solid complexes or soluble complexes that stabilize the activeingredient are formed with amorphous methyl-cyclodextrin.

DIMEB has other properties. Here, this is a crystalline product. Thetendency toward formation of inclusion complexes increases withincreasing lipophilia (Rekharsky, M.; Inoue, Y.; Chem. Rev. 1998, 98,1875-1918).

For example, the bibliographic reference EP121777 discloses theproduction of DIMEB. Starting from β-cyclodextrin, the hydroxy groups in2- and 6-positions are selectively methylated. The product is purifiedby crystallization. In the literature, DIMEB had been described as earlyas 1968 (Tetrahedron 1968, 24, 803-806). DIMEB has a high affinity forlipophilic substances. DIMEB has, i.a., a high affinity for cholesterol,so that cholesterol is extracted from the blood cell membranes in theorganism. In intravenous administration, DIMEB shows hemolytic effectsand forms precipitates with cholesterol. DIMEB is very readily solublein water. In addition, DIMEB has a negative temperature effect; it isvery readily soluble at 20° C. (>50 g/100 ml of water) and not verysoluble while being heated (<1 g/100 ml). At 20° C., DIMEB is present asa hydrated, readily soluble form; at higher temperatures, a less readilysoluble anhydrate is formed (Saenger et al., Langmuir 2002, 18,5974-5976).

In free form as an excipient, DIMEB can crystallize out because of thelower solubility while being heated during sterilization. The uniformsubstitution with DIMEB has the effect that it itself and also as acomplex can be readily crystallized, and the complexes generally areless readily soluble than DIMEB itself.

In the group of cyclodextrins and cyclodextrin derivatives, there are anumber of compounds with properties for dissolving that are comparableto DIMEB, some with partially better properties for dissolving thanDIMEB.

Modified cyclodextrins with an unsymmetrical substitution and/or anon-uniform substitution and also the complexes generally show a lowercrystallinity than modified cyclodextrins with symmetrical and/oruniform substitution. Thus, for example, the statistically methylatedβ-cyclodextrin (RAMEB) is readily water-soluble, and also the complexesof the RAMEBs tend only slightly toward crystallization.

Cyclodextrin complexes of vitamin D compounds or analogs thereof arepartially known. An attempt was made to improve the stability and thesolubility by complexing (Pharmazie [Pharmaceutics] 1993, 35, 779-787,GB-A 2,037,773).

Vitamin D compounds and analogs thereof are, for example, the naturalcalcitriol (1α-25-dihydroxyvitamin D₃), the calcifediol(25-hydroxyvitamin D₃), the cholecalciferol (vitamin D₃), thecalcipotriol (CAS 112965-21-6) and the tacalcitol (CAS-57333-96-7).

Additional analogs of the vitamin D series are disclosed in WO 94/07853,WO 01/07405 and WO 97/41096.

A compound according to WO 01/07405 is(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol(compound 1).

This calcitriol derivative is developed for treatment of psoriasis withtopical and oral administration.

Vitamin D compounds and most analogs thereof have instability towardair, temperature and exposure to light, as do many compounds of WO01/07405 and WO 97/41096.

After four months, a sample of compound 1, stored at room temperature,shows, for example, only a content of 60% at a previtamin content ofabout 2% in comparison to samples that are freshly produced or samplesthat are stored under inert conditions.

Vitamin D compounds or analogs thereof often have a 5Z,7E,10(19)-trienesystem, which, moreover, tends to isomerize to the previtamin. Insolution, these substances are subject to a natural isomerization to theprevitamin because of a sigmatropic 1,7-H shift (Curtin, M. L.; Okamura,W. H.: J. Am. Chem. Soc. 1991, 113, 6958-6966). Affected by this arevitamin D compounds and analogs thereof with a 5Z,7E,10(19)-trienesystem. The natural equilibrium is at a ratio of about 93:7 depending onsolvent, temperature, concentration and service life in solution. Thecis form of the vitamin form is thermodynamically favorable (Havinga, E.Experentia, 1973, 29, 1181). In contrast to calcitriols that are derivedfrom steroids, 19-nor-calcitriols do not show this isomerization (DeClerk, P. J. et al., J. Med. Chem. 1999, 42, 3539-3556).

For example, the compound 1 isomerizes to the compound 2.

In Patent Application WO 97/23242, complexes of isopropyl(5Z,7E,22E)-(1S,3R,24R)-1,3,24-trihydroxy-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylateare disclosed. In this application, the isomerization to the previtaminin particular is not discussed in more detail.

In 1980, Szejtli et al. described the vitamin D₃-β-cyclodextrin complex(Szejtly et al., Pharmazie 1980, 35, 779). The production is carried outin ethanolic solution (GB 2037773). An influence of thevitamin-previtamin equilibrium in connection with the complexing is notmentioned.

In the literature, references to the isomerization of vitamin D toprevitamin D under the influence of β-cyclodextrin can be found (Tian,X. Q.; Hollick, M. F.; J. Biolog. Chem., 1995, 270, 8706-8711). Thispublication is based on the in vivo isomerization of the previtamin tothe vitamin, which was tested as a model for the biomimeticisomerization. The previtamin-vitamin isomerization occurs in thephotolytic biogenesis of vitamin D₃ after a pericyclic ring opening ofthe 7-dehydrocholesterol in the triene system. In the photolytic openingof the steroid (provitamin), a secosteroid is produced that first ispresent as a previtamin after the cleavage of the bond at C9 and C10 andthen isomerizes to the vitamin. Because of the reversibility of thisisomerization, both isomers are present together in solution.

Studies on isomerization are described in the literature (Curtin, M. L.,Okamura, W. H., J. Am. Chem. Soc. 1991, 113, 6958-6966). Supplementaryliterature for previtamin formation of vitamin D compounds is found atthe following sites: J. Am. Chem. Soc. 113, 6958ff (1991); J. Biol.Chem. 270, 8706ff (1995); J. Am. Chem. Soc. 121, 4933 (1999);Tetrahedron Lett. 33, 5445ff (1992); J. Bone Miner. Res. 8, 1009 ff(1993); J. Med. Chem. 37, 2387ff (1994); BBRC 189, 1450ff (1992); J.Biol. Chem. 268, 13811 (1993); J. Biol. Chem. 268, 2022 (1993).

Example 1 of this application confirms that vitamin D₂ and calcitriolare subject to an isomerization to the previtamin in the complexing withnative cyclodextrins.

The presence of the active ingredient in isomer forms is not desirable.In the case of low-dose active ingredients for oral or systemicadministration, fluctuations unavoidably occur in the active ingredientconcentration (insufficient content uniformity), which have a greaterimpact, the lower the dose of the active ingredient that is present.

The object of this invention is to stabilize vitamin D compounds oranalogs thereof with a 5Z,7E,10(19)-triene system relative toatmospheric oxygen, temperature and light without an isomerization tothe previtamin taking place.

To solve this technical problem, the invention teaches a complex thatconsists of a vitamin D compound or a vitamin D analog with acyclodextrin derivative, whereby optionally the mean molar ratio ofvitamin D to the cyclodextrin derivative is in the range of 1:5 to 5:1,in particular 1:2 to 2:1, preferably 1:1.2 to 1.2:1.

The cyclodextrin derivative preferably contains n=6 or 7 glucopyranoseunits. In addition, a cyclodextrin derivative is preferred, whereby R1is a 6-O substituent, R2 is a 4-O substituent, and R3 is a 2-Osubstituent of the glucopyranose units (whereby the term m-O substituentmeans that the hydrogen on the oxygen atom, which is bonded to thecarbon atom with the numbering scheme m of a glucopyranose unit, isreplaced by the relevant substituents), whereby R1, R2 and R3 can be thesame or different and are any physiologically compatible radical, butnot —H at the same time, and are preferably —H, C1-C8-alkyl, linear orbranched, saturated or unsaturated, —SO₂OH, —PO(OH)₂, or —CO—R4 withR4=C1-C8-alkyl, whereby the C1-C8-alkyl can be substituted in one ormore places, on the same or on different C atoms with —OH, —COOH,—CONHR5, —NHCOR6, —SO₂OH, —PO(OH)₂ or tetrazol-5-yl, with R5=—H orC1-C4-alkyl and R6=carboxylphenyl, whereby R1, R2, and R3 can berandomized in various glucopyranose units, whereby an oxygen atom orseveral oxygen atoms of the glucopyranose units, in particular theoxygen atom 6-O, can be replaced by sulfur atoms, or with aphysiologically compatible salt of such a cyclodextrin derivative.Especially preferred is a cyclodextrin derivative, whereby n=7 and R1,R2, and R3 are the same or different but are not —H at the same time,and are —H or C1-C8-alkyl or C1-C8-hydroxyalkyl.

In particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, etc., fall under C1-C8 alkyl. C1-C8 Hydroxyalkyl isbased on C1-C8 alkyl, whereby one or more, preferably one, of the Catoms carries a hydroxyl group or several hydroxyl groups.

The object of this invention is further achieved by complexing of thevitamin D compounds and analogs thereof with methylated derivatives ofthe β-cyclodextrin.

Suitable methylated derivatives of the β-cyclodextrin are in particularheptakis-(2,6-di-O-methyl)-β-cyclodextrin (DIMEB), statisticallymethylated β-cyclodextrin (RAMEB) and permethylated β-cyclodextrin with21 methyl groups (TRIMEB).

The induction of an isomerization to the previtamin as in the case ofnative cyclodextrins virtually does not occur with these methylatedβ-cyclodextrin derivatives.

The isomerization of vitamin D compounds and analogs thereof to theprevitamin that is induced by native cyclodextrins thus can be avoidedfor all vitamin D compounds and analogs thereof with a5Z,7E,10(19)-triene system by means of methylated β-cyclodextrinderivatives. This means that with methylated β-cyclodextrin derivatives,these compounds can be stabilized relative to atmospheric oxygen,temperature and light without the drawbacks of an isomerization to theprevitamin.

Vitamin D analogs of general formula I,

-   -   in which    -   Y₁ and Y₂, independently of one another, each mean a hydrogen        atom or a group —C(O)R₅,    -   and Y₃ means a hydrogen atom or a hydroxy group, a halogen atom,        a group —OC(O)R₅ or an OR₅ group,        -   whereby        -   R₅ stands for an aromatic radical with 5 to 12 C atoms, or            for an aliphatic, straight-chain or branched, saturated or            unsaturated C₁-C₁₂ alkyl radical, which optionally is            interrupted by 1-2 oxygen atoms, 1-2 sulfur atoms, and/or            1-2 NH groups and/or optionally is substituted by 1-2            hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH            groups and/or 1-2 phenyl groups,        -   and the group Y₃ can be present both in the 2α-situation and            in the epimeric 2β-situation,    -   R₁ and R₂ together mean an exocyclic methylene group,    -   R₃ and R₄, independently of one another, each mean a hydrogen        atom, a fluorine, chlorine or bromine atom, an alkyl group with        1 to 4 carbon atoms, together a methylene group, or, together        with the quaternary carbon atom 20, a 3- to 7-membered,        saturated or unsaturated carbocyclic ring,    -   Q means a straight-chain alkylene group with 1 to 5 carbon        atoms,    -   X₁ and X₂ together mean a double-bonded keto-oxygen atom or,        independently of one another, a hydrogen atom, a hydroxy group,        an —O(CO)R₅ group, a fluorine, chlorine or bromine atom,        -   whereby X₁ and X₂ should each be, not simultaneously, a            hydroxy group or an —O(CO)R₅ group,    -   Z means a carbocyclic or heterocyclic, optionally aromatic or        heteroaromatic ring with 5 or 6 ring members or a condensed ring        system that consists of a 5- and a 6-membered ring or two        6-membered rings, which can be substituted by one or more        fluorine, chlorine, bromine or iodine atoms, one or more hydroxy        groups, one or more COOR₆ groups, one or more C₁-C₅-alkyl        groups, which in turn can be substituted by one or more        fluorine, chlorine, bromine, or iodine atoms, C₁-C₆-alkoxy        groups and/or COOR₆ groups,        -   whereby    -   R₆ stands for a C₁-C₆-alkyl group, a benzyl group or a phenyl        group,        as well as all possible epimers or diastereomers and mixtures        thereof,        can [be] especially advantageous.

These vitamin D analogs are disclosed in WO 01/07405. Also, however,vitamin D analogs according to the bibliographic references WO 97/00242,WO 97/41096, and WO 99/16745 can be used. All of these bibliographicreferences are herewith “incorporated by reference.”

The following vitamin D compounds and analogs thereof can also bestabilized as cyclodextrin derivative complexes, in particular as DIMEB,RAMEB or TRIMEB complexes:

Calcitriol[(5Z,7E)-(1S,3R)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol, CASNo. 32222-66-3)], calcifediol [25-hydroxy-vitamin D₃ (CAS No.19356-17-3)], cholecalciferol [vitamin D₃, (CAS-No. 67-97-0)];ergocalciferol [vitamin D₂,(5Z,7E,22E)-(3S)-9,10-secoergosta-5,7,10(19),22-tetraen-3-ol, (CAS No.50-14-6)]; 1α-hydroxycholecalciferol[(1alpha,3beta,5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1,3-diol, (CASNo. 41294-56-8)], calcipotriol[(1S,3R,5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol, (CAS 112965-21-6)], tacalcitol[(+)-(5Z,7E,24R)-9,10-secocholesta-5,7,10(19)-triene-1alpha,3beta-24-triolmonohydrate, (CAS No. 57333-96-7)].

Also, the following compounds are suitable:

-   (7E)-(1R,3R,24aR)-24a-(Oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(Oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (5Z,7E)-(1S,3R,24aR)-24a-(Oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,24aS)-24a-(Oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (7E)-(1R,3R,24aR)-24a-(Thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(Thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-1,3-Dihydroxy-24a-(thiazol-2-yl-)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (5Z    7E)-(1S,3R,24aR)-24a-(Thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,24aS)-24a-(Thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z    7E)-(1S,3R)-1,3-Dihydroxy-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one-   (7E)-(1R,3R,24aR)-24a-(4-Methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(4-Methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-1,3-Dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (5Z,7E)-(1S,3R,24aR)-24a-(4-Methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,24aS)-24a-(4-Methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R)-1,3-Dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one-   (7E)-(1R,3R,24aR)-24a-(Thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,2aS)-24a-(Thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-1,3-Dihydroxy-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (5Z,7E)-(1S,3R,24aR)-24a-(Thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,24aS)-24a-(Thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (7E)-(1R,2S,3R,24aR)-24a-Thien-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol-   (7E)-(1R,2S,3R,24aS)-24a-Thien-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol-   (7E)-(1R,2S,3R)-24a-Thien-2-yl-1,2,3-trihydroxy-24a-homo-9,10-secochola-5,7-dien-24a-one-   (7E)-(1R,3R,24aR)-24a-(4-Methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(4-Methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-1,3-Dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (5Z,7E)-(1S,3R,24aR)-24a-(4-Methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z    7E)-(1S,3R,24aS)-24a-(4-Methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R)-1,3-Dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one-   (7E)-(1R,2S,3R,24aR)-24a-(4-Methylthien-2-yl)-24a-homo-19-nor-9,10-secocola-5,7-diene-1,2,3,24-tetrol-   (7E)-(1R,2S,3R,24aS)-24a-(4-Methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol-   (7E)-(1R,2S,3R)-24a-(4-Methylthien-2-yl)-1,2,3-trihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (7E)-(1R,3R,24aR)-24a-(5-Ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(5-Ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aR)-24a-[5-(2-Hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-[5-(2-Hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-1,3-Dihydroxy-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (7E)-(1R,3R,24aR)-24a-(Benzothiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(Benzothiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-24a-(Benzothiazol-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (7E)-(1R,3R,24aR)-24a-(Benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(Benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-24a-(Benzofuran-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (7E)-(1R,3R,24aR)-24a-(Benzothiophen-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(Benzothiophen-2-yl)-24a-homo-19-nor-9,19-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-24a-(Benzothiophen-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (7E)-(1R,3R,24aR)-24a-(1-Methylbenzimidazol-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(1-Methylbenzimidazol-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-1,3-Dihydroxy-24a-(1-methylbenzimidazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (7E)-(1R,3R)-1-(1,3-Dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-[(4-methoxyphenyl)methoxy]-1H-pyrazole-4-carboxylic    acid ethyl ester-   (7E)-(1R,3R)-1-(1,3-Dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-hydroxy-1H-pyrazole-4-carboxylic    acid ethyl ester-   (7E)-(1R,3R,24aR)-24a-(4-Methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(4-Methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-1,3-Dihydroxy-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (7E)-(1R,2R,3R,24aR)-24a-(4-Methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol-   (7E)-(1R,RS,3R,24aS)-24a-(4-Methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol-   (7E)-(1R,3R,24aR)-24a-(4-Trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(4-Trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-1,3-Dihydroxy-24a-(4-trifluoromethylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (7E)-(1R,3R,24aR)-24a-(4-Methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(4-Methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-1,3-Dihydroxy-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (7E)-(1R,3R,20S,24aR)-24a-(Thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,20S,24aS)-24a-(Thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,20S)-1,3-Dihydroxy-24a-(thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (5Z,7E)-(1S,3R,20S,24aR)-24a-(Thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,20S,24aS)-24a-(Thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,20S)-1,3-Dihydroxy-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one-   (5Z,7E)-(1S,3R,24S)-24-(Thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol-   (5Z,7E)-(1S,3R,24R)-24-(Thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol-   (5Z    7E)-(1S,3R)-1,3-Dihydroxy-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one-   (7E)-(1R,3R,20S,24aR)-24a-(Oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,20S,24aS)-24a-(Oxazol-4-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,20S)-1,3-Dihydroxy-24a-(oxazol-4-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (5Z,7E)-(1S,3R,20S,24aR)-24a-(Oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z    7E)-(1S,3R,20S,24aS)-24a-(Oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,20S)-1,3-Dihydroxy-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one-   (5Z,7E)-(1S,3R,24R)-24-(Oxazol-4-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,24S)-24-(Oxazol-4-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z    7E)-(1S,3R)-1,3-Dihydroxy-24-(oxazol-4-yl)-9,10-secochola-5,7,10(19)-trien-24-one-   (7E)-(1R,3R,20S,24aR)-24a-(4-Methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,20S,24aS)-24a-(4-Methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,20S)-1,3-Dihydroxy-24a-(4-methylthiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (5Z,7E)-(1S,3R,20S,24aR)-(4-Methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,20S,24aS)-24a-(4-Methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,20)-1,3-Dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one-   (5Z,7E)-(1S,3R,24R)-24-(4-Methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,24S)-24-(4-Methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R)-1,3-Dihydroxy-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one-   (7E)-(1R,3R,20S,24aR)-24a-(4-Methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,20S,24aS)-24a-(4-Methylthien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,20S)-1,3-Dihydroxy-24a-(4-methylthien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (5Z,7E)-(1S,3R,20S,24aR)-24a-(4-Methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,20S,24aS)-24a-(4-Methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,20S)-1,3-Dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one-   (5Z,7E)-(1S,3R,24R)-24-(4-Methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,24S)-24-(4-Methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R)-1,3-Dihydroxy-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one-   (7E)-(1R,3R,20S,24aR)-24a-(Thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,20S,24aS)-24a-(Thien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,20S)-1,3-Dihydroxy-24a-(thien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one-   (5Z,7E)-(1S,3R,20S,24aR)-24a-(Thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,20S,24aS)-24a-(Thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,20S)-1,3-Dihydroxy-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one-   (5Z,7E)-(1S,3R,24R)-24-(Thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol-   (5Z,7E)-(1S,3R,24S)-24-(Thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol    (5Z,7E)-(1S,3R)-1,3-Dihydroxy-24-(Thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one-   (5Z,7E)-(1S,3R,24S)-24-(4-Methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol-   (5Z,7E)-(1S,3R,24R)-24-(4-Methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol-   (5Z,7E)-(1S,3R)-1,3-Dihydroxy-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one-   (5Z,7E)-(1S,3R,24S)-24-(Thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol-   (5Z,7E)-(1S,3R,24R)-24-(Thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol-   (5Z,7E)-(1S,3R)-1,3-Dihydroxy-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one-   (5Z,7E)-(1S,3R,24S)-24-(4-Methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol-   (5Z,7E)-(1S,3R,24R)-24-(4-Methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol-   (5Z,7E)-(1S,3R)-1,3-Dihydroxy-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one-   (7E)-(1R,3R,24aR)-24a-Fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3-diol-   (7E)-(1R,3R,24aS)-24a-Fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3-diol-   (5Z,7E)-(1S,3R,24aR)-24a-Fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3-diol-   (5Z,7E)-(1S,3R,24aS)-24a-Fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3-diol-   (7E)-(1R,3R,24aR)-24a-(Acetyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(Acetyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aR)-24a-(2,2-Dimethylpropanoyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R,24aS)-24a-(2,2-Dimethylpropanoyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol-   (7E)-(1R,3R)-2-Bromo-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

Complexes according to the invention that consist of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triolwith DIMEB, RAMEB or TRIMEB are especially preferred.

A complex that consists of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triolwith DIMEB is especially preferred.

The complexes according to the invention show a superior stability anddurability in comparison to the free and noncomplexed active ingredient.

The production of the complexes according to the invention is carriedout with methods that are known in the literature (e.g., A. R. Hedges,Chem. Rev. 1998, 98, 2035-2045; W. Saenger, Angew. Chem. [AppliedChemistry] 42, 343-361 (1980):

1. Co-precipitation method

2. Suspension method

3. Kneading process (paste method)

4. Dry mixing process (dry mixing method)

Soluble complexes can be isolated by freeze-drying.

The production of the cyclodextrin-guest complexes depends on theproperties of the guest components, the cyclodextrin and the propertiesof the complex.

Water-soluble substances can be dissolved—directly or dissolved in anaqueous solvent or solvent mixture—in hot or cold, concentrated aqueoussolutions of the cyclodextrin derivative in equimolar amounts or up to a10-fold excess. Solid complexes that crystallize out immediately or withslow cooling or evaporation, or soluble complexes, which can be isolatedby drying processes, can be formed. In this case, the ratio of use ofguest components to the cyclodextrin derivative can have an influence onwhat type of complex is formed. Solid complexes can be filtered off andoptionally dried. Soluble complexes can be isolated by drying processes.

Solid complexes and soluble complexes can also be producedsimultaneously.

Substances that are not water-soluble are dissolved in, for example,ether, and are layered under or above an aqueous concentratedcyclodextrin derivative solution or shaken therewith.

For industrial production, the kneading process is offered.

Since the complexes of DIMEB according to the invention generally have alower water-solubility than the DIMEB itself, precipitation methods, forexample, are suitable for production. The solubility of the DIMEB is 60g/100 ml of water (Saenger et al., Langmuir 2002, 18, 5974-5976, Uekama,K.: Irie, T. in Cyclodextrins and their Industrial Uses, Duchene, D.,Ed.; Editions Santé, Paris, 1987, p. 395).

The compounds according to the invention with DIMEB are preferablyproduced by the DIMEB being dissolved in water at a temperature ofbetween 0° and 80° C., and the vitamin D compound or analogs thereof,dissolved in a C1-C10-alcohol such as methanol or ethanol or a C3-C10ketone, such as acetone or methylethylketone, being added in measuredquantities to the aqueous cyclodextrin derivative solution. It is cooledto 0-10° C. for 1-24 hours while being stirred, and the complex isfiltered off and optionally dried.

In the complexing, DIMEB can be used in excess with a degree ofmethylation of 1.8-2.2, whereby generally a 1:1 complex results. ExcessDIMEB with a methyl group number that deviates by 14 preferably remainsin the solution, by which a purification effect occurs relative to thecyclodextrin derivative. The existing methyl homologs that are caused byproduction and that deviate from the 2^(nd) degree of methylation arereduced in the complexing. As a result, the molecular weightdistribution of the cyclodextrin derivative is more narrow in thecomplex.

The compounds according to the invention with RAMEB or TRIMEB arepreferably produced by concentration by evaporation of the solution,freeze-drying, spray-drying or vacuum drying.

To this end, the vitamin D compound or analogs thereof are addedtogether with the (methylated) cyclodextrin derivative in a solubleform. In this case, both complex components can be dissolved in the sameor different solvent(s), preferably aqueous solvents, and then arecombined. There is also the possibility, however, first to dissolve oneof the components and to add the other in solid form. After 1-24 hoursof stirring, the soluble complex, for example, is freeze-dried andobtained as a residue.

The complexes according to the invention are suitable not only for theproduction of systemically applicable preparations; they can also beused for the production of dosage forms with superior properties thatare to be administered topically. The complexes are suitable forpreparation of solid and even liquid formulations.

In the storage of preparations, an additional reduction of the activeingredient concentration is often observed as a result of the oxidationas a breakdown pathway of the active ingredient. The durability of theactive ingredient complex in the formulation is increased.

It was found for the oral administration that solid preparation formsthat contain powdery or crystalline cyclodextrin derivative complexesare advantageous.

The complexes from compound 1 with methylated β-cyclodextrins are notknown a priori. These complexes are distinguished compared to complexesthat are known a priori in that in the case of topical and systemicadministration, a better durability of the active ingredient is ensured.They are distinguished by superior properties; in particular noincreased previtamin formation occurs.

The conversion into complexes allows a better manageability and meteringcapacity of the active ingredient that is active in small dosage units.Also, the complexes according to the invention show a better stabilitythan the noncomplexed substance. For the production of pharmaceuticalformulations, the complexes can be mixed with other pharmaceuticaladjuvants. The production of the pharmaceutical preparations is ingeneral known a priori.

While native cyclodextrins favor the previtamin formation, methylatedβ-cyclodextrins in the complexing do not show any additional previtaminformation. In the examples below, a complex, according to the invention,that consists of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland methylated β-cyclodextrins is described by way of example.Especially with DIMEB, complexes of higher crystallinity are formed,which are advantageously suitable for the production of solid andsemisolid formulations. In the described form as a DIMEB complex, theactive ingredient has a superior stability compared to the free activeingredient.

In addition to the(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol,the natural calcitriol (1α,25-dihydroxyvitamin D₃), as well as a numberof structures that are derived from vitamin D, can also be stabilized asa DIMEB complex. The use of DIMEB as a modified cyclodextrin has theadvantage that in the production of the complex, no isomerization to theprevitamin occurs. These complexes have a superior durability incomparison to the noncomplexed compounds.

In addition, the invention relates to a pharmaceutical composition thatcontains a complex according to the invention. It can contain additionalgalenical adjuvants and/or vehicles. The selection thereof depends onthe selected dispensing form. In this case, the galenical preparation ofthe pharmaceutical composition according to the invention can be carriedout in a more technical way.

As counterions for ionic compounds, for example, Ca⁺⁺, CaCl⁺, Na⁺, K⁺,Li⁺ or cyclohexylammonium, or Cl⁻, Br⁻, acetate, trifluoroacetate,propionate, lactate, oxalate, malonate, maleinate, citrate, benzoate,salicylate, etc., are suitable. Suitable solid or liquid galenicalpreparation forms are, for example, granulates, powders, coated tablets,tablets, (micro-)capsules, suppositories, syrups, juices, suspensions,emulsions, drops or solutions for injection (i.v., i.p., i.m., s.c.) oratomization (aerosols), preparation forms for dry-powder inhalation,transdermal systems, as well as preparations with protracted release ofactive ingredients, in whose production common adjuvants such asvehicles, explosives, binders, coating means, swelling agents,lubricating agents or lubricants, flavoring correctives, sweeteners andsolubilizers are used. As adjuvants, for example, magnesium carbonate,titanium dioxide, lactose, mannitol and other sugars; talc, milkprotein, gelatin, starch, cellulose and derivatives thereof; animal andplant oils such as liver oil, sunflower oil, peanut oil or sesame oil;polyethylene glycols and solvents, such as, for example, sterile water;and monovalent or multivalent alcohols, for example glycerol, can bementioned. A pharmaceutical agent according to the invention can thus beproduced in that at least one complex that is used according to theinvention in a defined dose is mixed with a pharmaceutically suitableand physiologically compatible vehicle and optionally other suitableactive ingredients, additives or adjuvants with a defined dose and isprepared in the desired dispensing form.

As diluents, polyglycols, ethanol, water and buffer solutions aresuitable. Suitable buffer substances are, for example,N,N′-dibenzylethylenediamine, diethanolamine, ethylenediamine,N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate,sodium bicarbonate or sodium carbonate. The operation can be performedeven without diluents, however.

Physiologically compatible salts, either the vitamin D or vitamin Danalog or the cyclodextrin derivative, are salts with inorganic ororganic acids, such as hydrochloric acid, sulfuric acid, acetic acid,citric acid, p-toluenesulfonic acid, or with inorganic or organic bases,such as NaOH, KOH, Mg(OH)₂, diethanolamine, ethylenediamine or withamino acids, such as arginine, lysine, glutaminic acid, etc., or withinorganic salts, such as CaCl₂, NaCl or their free ions, such as Ca²⁺,Na⁺, Cl⁻, SO₄ ²⁻ or combinations thereof. They are produced according tostandard methods.

In the pharmaceutical composition, an administration unit can contain0.1 μg to 1000 μg, preferably 1.0 μg to 500 μg, of the vitamin Dcompound or the vitamin D analog.

A pharmaceutical composition according to the invention is suitable forprophylaxis and/or treatment of a disease from the group that consistsof “diseases that are characterized by hyperproliferation and deficientcell differentiation, in particular hyperproliferative diseases of theskin, such as psoriasis, pituriasis subia pilasis, acne, ichthyosis;pruritus; tumor diseases and precancerous diseases, such as intestinaltumors, breast cancer, lung tumors, prostate cancer, leukemia, T-celllymphoma, melanoma, beta cell carcinoma, squamous carcinoma, actinickeratoses, cervical dysplasias, metastasizing tumors of any type;diseases that are characterized by disruption of the equilibrium of theimmune system, in particular eczemas and diseases of the atopic group;and inflammatory diseases, such as rheumatoid arthritis; respiratorydiseases such as asthma; autoimmune diseases such as multiple sclerosis,diabetes mellitus type I, myasthenia gravis, lupus erythematosus,sclerodermia; bullous skin diseases such as pemphigus, pemphigoid;rejection reactions in the case of autologous, allogenic or xenogenictransplants as well as AIDS.” It can be used for treatment and/orprophylaxis of these diseases, whereby one or more administrationunit(s) of the pharmaceutical composition is dispensed to an individualwho is likely to come down with the disease or who is suffering from it.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the isomerization of Compound 1 in the presence of CD, and

FIGS. 2-4 show x-ray diffraction patterns of crystalline forms ofCompound 1.

The examples below represent preferred compositions of the inventionwithout, however, limiting the invention to these examples.

EXAMPLE 1

Complexing Ergocalciferol and Calcitriol with Native and Methylatedβ-Cyclodextrins

1.1 Complex of Ergocalciferol[(5Z,7E,22E)-(3S)-9,10-Secoergosta-5,7,10(19),22-tetraen-3-ol)] withβ-Cyclodextrin (Ratio of Use 1:1)

500 mg (1.26 mmol) of ergocalciferol is dissolved in 3 ml of ethanol andadded at 22° C. to 1.43 g (1.26 mmol) of β-cyclodextrin in 80 ml ofwater. It is stirred for 2 hours at 22° C. and for 2 hours at 0° C. Thesolid is suctioned off and washed with 5 ml of cold water. After drying,1.73 g (90% of theory) is obtained as a white solid. After HPLC (Stat.phase Chiracel JHRH 150×4.6 mm ID, detection 244 nm, eluantwater/acetonitrile, flow: 1 ml/minute, gradient t₀=70+30 v/v, linearincrease of the gradient over 10 minutes t_(10 min) to 60+40 v/v,isocratic t_(10 min-30 min) 60+40 v/v), the solid, in addition toergocalciferol (t_(Ret.)=26 minutes), contains 24% of the previtaminform (t_(Ret.)=23 minutes).

1.2 Complex of Ergocalciferol[(5Z,7E,22E)-(3S)-9,10-Secoergosta-5,7,10(19),22-tetraen-3-ol)] withβ-Cyclodextrin (Ratio of Use 1:2)

500 mg (1.26 mmol) of ergocalciferol is dissolved in 3 ml of ethanol andadded at 22° C. to 2.86 g (2.52 mmol) of β-cyclodextrin in 40 ml ofwater. It is stirred for 2 hours while being cooled to 20° C. andstirred for 2 hours at 0° C. The solution is freeze-dried. 3.3 g ofproduct (97% of theory) is obtained. After HPLC (see 1.1), thelyophilizate contains 29% of the previtamin form.

1.3 Complex of Ergocalciferol[(5Z,7E,22E)-(3S)-9,10-Secoergosta-5,7,10(19),22-tetraen-3-ol)] withDIMEB (Ratio of Use 1:1)

100 mg (0.25 mmol) of ergocalciferol is dissolved in 0.6 ml of ethanoland added at 22° C. to 335.7 mg (0.25 mmol) of DIMEB in 1 ml of water.It is stirred for 2 hours at 22° C. and for 2 hours at 0° C. Afterfreeze-drying, 445 mg of the ergocalciferol-DIMEB complex is obtained(99.9% of theory). After HPLC (see 1.1), the lyophilizate contains 0.3%of the previtamin form.

1.4 Complex of Calcitriol[(5Z,7E)-(1S,3R)-9,10-Secocholesta-5,7,10(19)-triene-1,3,25-triol)] withβ-Cyclodextrin (Ratio of Use 1:1.16)

32.7 mg (0.028 mmol) of β-cyclodextrin is dissolved at 30° C. in 2 ml ofwater under nitrogen atmosphere. 10 mg (0.024 mmol, MW 416.65) ofcalcitriol (dissolved in 100 μl of ethanol) is added in drops to theclear solution over 10 minutes. It is stirred for 2 hours at 22° C. andfor 2 hours at 0-3° C., the solid is filtered off, and it is washed 2times with 100 μl each of cold water. After drying at 20° C. and 0.5mbar (24 hours), 26.6 mg of calcitriol-β-CD complex (71.5% of theory) isobtained. After the solid is dissolved in methanol and after an HPLCstudy (Stat. Phase Chiracel JHRH 150×4.6 mm ID, detection 244 nm, eluantwater/acetonitrile, flow: 1 ml/minute, gradient t₀=70+30 v/v, linearincrease of the gradient over 10 minutes t_(10 min) to 60+40 v/v,isocratic t_(10 min-30 min) 60+40 v/v), the solid contains 23% of theprevitamin form (t_(Ret.)=12 minutes) in addition to calcitriol(t_(Ret.)=17 minutes).

1.5 Complex of Calcitriol[(5Z,7E)-(1S,3R)-9,10-Secocholesta-5,7,10(19)-triene-1,3,25-triol)] withDIMEB (Ratio of Use 1:1.16)

38.34 mg (0.028 mmol) of DIMEB is dissolved at 30° C. in 0.25 ml ofwater under nitrogen atmosphere. 50 μl of ethanol, dissolved [in] 10 mg(0.024 mmol, MW 416.65) of(5Z,7E)-(1S,3R)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol, isadded in drops to the clear solution. It is stirred for 2 hours at 22°C. and for 2 hours at 0° C., the solid is filtered off, and it is washed2 times with 50 μl each of cold water. After drying at 20° C. and 0.5mbar (24 hours), 10.7 mg of solid (42% of theory) is obtained. After thecomplex is dissolved in methanol and after an HPLC study, the solidcontains 0.2% of the previtamin form. After the filtrate isfreeze-dried, another 27 mg of lyophilizate is obtained.

Without the presence of β-cyclodextrin, ergocalciferol and calcitriol donot show any significant previtamin formation. With the nativeβ-cyclodextrin, an undesirable isomerization occurs during thecomplexing. As a complexing agent, however, DIMEB does not induce anyisomerization (Table 1). TABLE 1 Isomerization of Ergocalciferol andCalcitriol Ratio % Previtamin in the of Use Isolated ComplexErgocalciferol β-Cyclodextrin (1.1) 1:1 24 β-Cyclodextrin (1.2) 1:2 29DIMEB (1.3) 1:1 0.3 Without Cyclodextrin — 0.2 (in Solution) Calcitriolβ-Cyclodextrin (1.4)   1:1.16 23 DIMEB (1.5)   1:1.16 0.2 WithoutCyclodextrin — 0.3 (in Solution)

EXAMPLE 2

Complexing of Compound 1 with Native β-Cyclodextrins

2.1 Complex with(Thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland β-Cyclodextrin (Ratio of Use 1:1.1)

262 mg (0.23 mmol) of β-cyclodextrin is dissolved in 15 ml of water. At25° C., 100 mg (0.21 mmol) of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol(dissolved in 0.5 ml of ethanol) is added. It is stirred for 2 hours atroom temperature, then for 2 hours at 0° C. The solid is filtered off,washed with 1 ml of cold water and dried. 290 mg (85% of theory) ofsolid is obtained. The content of the solid in the previtamin (compound2) is 20% (HPLC, Stat. Phase Chiracel JHRH 150×4.6 mm ID, detection 244nm, eluant water/acetonitrile, flow: 1 ml/minute, gradient to =70+30v/v, linear increase of the gradient over 10 minutes t_(10 min) to 60+40v/v, isocratic t_(10 min-30 min) 60+40 v/v, t_(Ref.) Compound 2: 11.65minutes, t_(Ref.) Compound 1: 18.19 minutes). The sample preparation iscarried out by dissolving the complex in 100% methanol.

2.2 Complex with(Thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland 3-Cyclodextrin (Ratio of Use 1:2.3)

554 mg (0.48 mmol) of β-cyclodextrin is dissolved in 30 ml of water. At25° C., 100 mg (0.21 mmol) of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol(dissolved in 0.5 ml of ethanol) is added. It is stirred for 2 hours atroom temperature, then for 2 hours at 0° C. The solid is filtered off,washed with 1 ml of cold water, and dried. 454 mg of product is obtainedas a solid. The HPLC study (see 2.1) of the solid indicates 30%previtamin (compound 2). The sample preparation is carried out bydissolving the complex in 100% methanol.

2.3 Complex with(Thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland β-Cyclodextrin (Ratio of Use 1:10)

2.38 g (2.1 mmol) of β-cyclodextrin is suspended in 30 ml of water. At25° C., 100 mg (0.21 mmol) of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol(dissolved in 1 ml of ethanol) is added. It is stirred for 2 hours atroom temperature, then for 2 hours at 0° C. The solution isfreeze-dried. 2.45 g (98% of theory) of lyophilizate is obtained. TheHPLC study (see 2.1) of the lyophilizate indicates 80% of the previtaminform (compound 2). The sample preparation is carried out by dissolvingthe complex in 100% methanol.

2.4 Complex with(Thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland γ-Cyclodextrin (Ratio of Use 1:1.1)

100 mg (0.21 mmol) of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol(dissolved in 1 ml of ethanol) is added to 299 mg (0.23 mmol) ofγ-cyclodextrin in 1.4 ml of water at 25° C. It is stirred for 2 hours atroom temperature, then for 2 hours at 0° C., and the solid is filteredoff. After drying, 309 mg (83% of theory) is obtained as a solid. TheHPLC study of the solid (see 2.1) indicates 25% of the previtamin form(compound 2).

In tests for complexing compound 1 with native β-cyclodextrin (β-CD) andγ-cyclodextrin (γ-CD), an increased previtamin formation to form thecompound 2 is observed. The isomerization of compound 1 in the presenceof cyclodextrins is compiled in Table 2 and shown graphically in FIG. 1.

2.5 Complex with(Thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland γ-Cyclodextrin (Ratio of Use 1:2.3)

100 mg (0.21 mmol) of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol(dissolved in 1 ml of ethanol) is added to 633 mg (0.49 mmol) ofγ-cyclodextrin in 2.7 ml of water at 25° C. It is stirred for 2 hours atroom temperature, then for 2 hours at 0° C., and the solid is filteredoff. After drying, 562 mg (85% of theory) of solid is obtained. The HPLCstudy (see 2.1) of the solid indicates 25% of the previtamin (compound2). TABLE 2 Isomerization of Compound 1 in the Presence of Nativeβ-Cyclodextrins Cyclodextrin Inner Solubility in Cavity Ratio % Water(20° C.)* (A) of Use Previtamin Compound 1 β-Cyclodextrin (2.1) 1.85g/100 ml 6.0-6.4 1:1.1 20 β-Cyclodextrin (2.2) 1:2.3 30 β-Cyclodextrin(2.3) 1:10  80 γ-Cyclodextrin (2.4) 23.3 g/100 ml 7.5-8.3 1:1.1 25γ-Cyclodextrin (2.5) 1:2.3 25 Without CD — — 0.2 (in Solution)*(Source: Szejtly, J., Cyclodextrin Technology, Davies, J. E., Ed;Kluwer Academic Press, Dordrecht, The Netherlands 1988).

EXAMPLE 3

Complex of Compound 1 with Methylated Cyclodextrins

Cyclodextrin complexes of compound 1 with the cyclodextrins DIMEB, RAMEBand TRIMEB are produced and characterized (Table 3).

3 a) Production 3 a) 1. Complex that Consists of(Thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland DIMEB (Ratio of Use 1:1.2)

1.7 g (1.27 mmol) of heptakis-(2,6-di-O-methyl)-B-cyclodextrin isdissolved in 9 ml of water. At 25° C., 500 mg (1.06 mmol) of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol,dissolved in 1.5 ml of ethanol, is added in drops over a period of 5minutes. It is stirred for 2 hours at 20-25° C., and it is stirred foranother 2 hours while being cooled to 0-5° C. The solid is filtered offand rewashed with a little cold water. It is dried for 24 hours at 20°C. and 15 mbar. 1.9 g (98% of theory) is obtained as a solid.

The XPRD diagram of this solid indicates the presence of a crystallineform (recording of data performed in transmission mode with an automatedpowder diffractometer with use of germanium-monochromatizedCuKα1-radiation (=1.5406 Å); x-ray tubes with a copper anode operated at40 kV and 30 mA, the 2Θ measurements carried out with the linearsite-sensitive detector in the range of 3°≦2Θ≦35° (step width 0.5°).After dissolving in methanol, the solid shows a content (HPLC, p. 2.1)of 25.9% (calc. 26%) of compound 1.

3 a) 2. Complex that Consists of(Thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland DIMEB (Ratio of Use 1:2.35)

529 mg (0.4 mmol) of heptakis-(2,6-di-O-methyl)-β-cyclodextrin isdissolved in 5 ml of water. At 25° C., 81.4 mg (0.17 mmol) of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol,dissolved in 0.8 ml of ethanol, is added in drops over a period of 5minutes. It is stirred for 2 hours at 20-25° C. and stirred for another2 hours while being cooled to 0-5° C. The solid is filtered and rewashedwith a little cold water. It is dried for 24 hours at 20° C. and 15mbar. 300 mg (98% of theory) is obtained. The XPRD diagram (see 3.a) 1.)of this compound shows the presence of a crystalline form.

In the HPLC study (HPLC, p. 2.1), the solid indicates a content of 25.7%(calc. 26%) of compound 1.

3 a) 3. Complex with(Thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland RAMEB (Ratio of Use 1:1.05)

300 mg (22 mmol) of RAMEB (MW 1303) is dissolved in 2 ml of water. 100mg (0.21 mmol) of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene1,3,25-triol is dissolved in 1 ml of ethanol and added to the RAMEBsolution. The solution is stirred for 4 hours at 0° C. and thenfreeze-dried. 390 mg of lyophilizate (100% of theory) is obtained.

3 a) 4. Complex with(Thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland TRIMEB (Ratio of Use 1:1)

300 mg (0.21 mmol) of TRIMEB (MW 1429.54) is dissolved in 8 ml of water.100 mg (0.21 mmol) of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triolis added, dissolved in 1 ml of ethanol. The solution is stirred for 4hours and then freeze-dried. 387 mg of lyophilizate (99% of theory) isobtained.

3 b) Characterization 3 b) 1. X-Ray Diffractometry

The solid form of the complex is analyzed with x-ray powderdiffractometry. In FIGS. 2, 3, and 4, examples of crystalline forms ofcompound 1, the DIMEB and the complex are shown.

3 b) 2. Previtamin Formation

For analytical study, the complexes can be dissolved in methanol or DMFand can be used in these solutions for the HPLC analysis (see 2.1). Thecontent of the complexes that are obtained can be determined incomparison to the pure substance.

The complexes of compound 1 with methylated cyclodextrins aredistinguished in that no isomerization in the previtamin takes place.TABLE 3 Complexes of Compound 1 with Methylated Cyclodextrins withoutAdditional Previtamin Formation CD- Water Degree of Solubility %Previtamin in methyl- (g/100 ml), Ratio of the Isolated YieldCyclodextrin ation (25° C.) Use Complex Solid Form (%) Compound 1 DIMEB(3 a) 1) 2 25 1:1   0.3 Crystalline 98 a) DIMEB (3 a) 2) 2 25 1:2.35 0.2Crystalline 98 a) RAMEB (3 a) 3) 1.7-1.93 10 1:1.05 0.5 Amorphous 100b)  TRIMEB (3 a) 4) 3 200 1:1   0.3 Amorphous 99 b) Without CD — — — 0.3— —a) Yield After Filtration and Dryingb) After Freeze-Drying

3b) 3. Stability

In Table 4 below, the stabilities of the DIMEB complex from Example 3a) 1. and the non-complexed active ingredient are compiled:

Both in solid form (Exp. Nos. 3, 4 and 7 in Table 4) and in aqueoussolution (what concentration?), the complex from Example 3a) 1. is morestable than the noncomplexed compound 1 (Exp. Nos. 10-14 in Table 4).TABLE 4 Stability of the DIMEB Complex from Example 3 a) 1 ComplexPurity from Example Compound 1* Compound 1* Exp. No. Conditions 3 a) 1.By-Products Purity By-Products Start¹⁾ — 96.44 2.61 96.12 3   2 30 d 40°C. 96.48% 2.5% 96.08 3.08 3 3 d/80° C./75% rel F. 96.25 2.86 22.5577.45  4 7 d/80° C./75% rel F. 96.14 2.89 4.66 95.34  5 15 d/40° C./75%rel F. 96.82 2.69 96.61 2.9  6 15 d/60° C./75% rel F. 96.69 2.81 96.342.96 7 15 d/80° C./75% rel F. 96.69 2.72 0 100    8 30 d/40° C./75% relF. 94.81 2.29 96.7 3.00 9 30 d/60° C./75% rel F. 94.84 2.27 96.23 2.9810 15 d/40° C. aqueous *** 96.55 2.81 92.78  2.92** 11 15 d/60° C.aqueous *** 96.11 3.15 77.12  18.69** 12 15 d/80° C. aqueous *** 96.083.16 3.28  96.72** 13 30 d/40° C. aqueous *** 95 2.26 91.96  3.20** 1430 d/60° C. aqueous *** 94.9 2.6 59.76  37.26***Difference to 100 corresponds to the isomer portion, which is presentdue to factors related to synthesis as starting contaminants**Concentration of 20 μg per ml of solution*** 80 μg of DIMEB complex per ml of solution

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius and, all parts and percentages areby weight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding German application No. 10200501777.5,filed Apr. 13, 2005 and U.S. Provisional Application Ser. No.60/673,360, filed Apr. 21, 2005 are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. Complex that consists of a vitamin D compound or a vitamin D analogwith a cyclodextrin derivative, whereby optionally the mean molar ratioof vitamin D or vitamin D analog to cyclodextrin derivative is in therange of 1:5 to 5:1, in particular 1:2 to 2:1, and preferably 1:1.2 to1.2:1.
 2. Complex according to claim 1, whereby the cyclodextrinderivative contains n=6 or 7 glucopyranose units.
 3. Complex accordingto claim 1, with a cyclodextrin derivative, in which R1 is a 6-Osubstituent, R2 is a 4-O substituent, and R3 is a 2-O substituent of theglucopyranose units, whereby R1, R2 and R3 can be the same or differentand can be any physiologically compatible radical, but all three cannotbe —H at the same time, and are preferably —H, C1-C8-alkyl, linear orbranched, saturated or unsaturated, —SO₂OH, —PO(OH)₂, or —CO—R4 withR4=C1-C8-alkyl, whereby the C1-C8-alkyl can be substituted in one ormore places, on the same or on different C atoms with —OH, —COOH,—CONHR5, —NHCOR6, —SO₂OH, —PO(OH)₂ or tetrazol-5-yl, with R5=—H orC1-C4-alkyl and R6=carboxyphenyl, whereby R1, R2 and R3 can berandomized in different glucopyranose units, whereby an oxygen atom orseveral oxygen atoms of the glucopyranose units, in particular theoxygen atom 6-O, can be replaced by sulfur atoms, or with aphysiologically compatible salt of such a cyclodextrin derivative. 4.Complex according to claim 1, with a cyclodextrin derivative, wherebyn=7 and R1, R2, and R3 are the same or different, but all three are not—H at the same time, and are —H or C1-C8 alkyl or C1-C8 hydroxyalkyl. 5.Complex that consists of vitamin D compounds or analogs thereof with a5Z,7E,10(19)-triene system and methylated derivatives of theβ-cyclodextrin.
 6. Complex according to claim 1, whereby the complex, asa vitamin D analog, contains a compound according to general formula I

in which Y₁ and Y₂, independently of one another, each mean a hydrogenatom or a group —C(O)R₅, and Y₃ means a hydrogen atom or a hydroxygroup, a halogen atom, a group —OC(O)R₅ or an OR₅ group, whereby R₅stands for an aromatic radical with 5 to 12 C atoms, or for analiphatic, straight-chain or branched, saturated or unsaturated C₁-C₁₂alkyl radical, which optionally is interrupted by 1-2 oxygen atoms, 1-2sulfur atoms, and/or 1-2 NH groups and/or optionally is substituted by1-2 hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH groupsand/or 1-2 phenyl groups, and the group Y₃ can be present both in the2α-situation and in the epimeric 2β-situation, R₁ and R₂ together meanan exocyclic methylene group, R₃ and R₄, independently of one another,each mean a hydrogen atom, a fluorine, chlorine or bromine atom, analkyl group with 1 to 4 carbon atoms, together a methylene group, or,together with the quaternary carbon atom 20, a 3- to 7-membered,saturated or unsaturated carbocyclic ring, Q means a straight-chainalkylene group with 1 to 5 carbon atoms, X₁ and X₂ together mean adouble-bonded keto-oxygen atom or, independently of one another, ahydrogen atom, a hydroxy group, an —O(CO)R₅ group, a fluorine, chlorineor bromine atom, whereby X₁ and X₂ should each be, not simultaneously, ahydroxy group or an —O(CO)R₅ group, Z means a carbocyclic orheterocyclic, optionally aromatic or heteroaromatic ring with 5 or 6ring members or a condensed ring system that consists of a 5- and a6-membered ring or two 6-membered rings, which can be substituted by oneor more fluorine, chlorine, bromine or iodine atoms, one or more hydroxygroups, one or more COOR₆ groups, one or more C₁-C₅-alkyl groups, whichin turn can be substituted by one or more fluorine, chlorine, bromine,or iodine atoms, C₁-C₆-alkoxy groups and/or COOR₆ groups, whereby R₆stands for a C₁-C₆-alkyl group, a benzyl group or a phenyl group, aswell as all possible epimers or diastereomers and mixtures thereof. 7.Complex according to claim 1, whereby the complex, as a vitamin Danalog, contains(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol.8. Complex according to claim 1, whereby the complex, as a vitamin Dcompound or analog thereof, contains calcitriol, ergocalciferol,calcipotriol, tacalcitol, 25-hydroxy-vitamin D₃, or1α-hydroxycholecalciferol.
 9. Complex according to claim 1, whereby thecomplex, as a methylated β-cyclodextrin derivative, contains DIMEB. 10.Complex according to claim 9, characterized in that the DIMEB has adegree of methylation of more than 1.8 and of less than 2.2.
 11. Complexaccording to claim 1, whereby the complex, as a methylatedβ-cyclodextrin derivative, contains RAMEB or TRIMEB.
 12. Complex thatconsists of(thiazol-2-yl)-26,27-dinor-9,10-secocholesta-5,7,10(19)-triene-1,3,25-trioland DIMEB, RAMEB or TRIMEB.
 13. Process for the production of a complexaccording to claim 1, wherein a) the preferably methylated derivative ofthe cyclodextrin, preferably the β-cyclodextrin, is dissolved at atemperature of between 0° and 80° C. in water, and the vitamin Dcompound or analog thereof, dissolved in methanol, ethanol, aC1-C10-alcohol or a C3-C10 ketone, such as, e.g., acetone, ormethylethylketone, is added in measured quantities to the aqueouscyclodextrin derivative solution, b) is stirred for 1-24 hours whilebeing cooled at 0-30° C., c) the solid that is obtained is filtered off,and d) optionally is dried.
 14. Process according to claim 13, whereinthe vitamin D compound, or analogs thereof, is dissolved in ethanol. 15.Process according to claim 13, wherein as a methylated derivative of theβ-cyclodextrin, DIMEB is used.
 16. Process for the production of acomplex according to claim 1, wherein a) the methylated derivative ofthe β-cyclodextrin is added together with the vitamin D compound oranalogs thereof in a soluble form, b) is stirred for 1-24 hours, and c)the complex is obtained from the solution by concentration byevaporation of the solution, freeze-drying, spray-drying orvacuum-drying.
 17. Process for the production of a complex according toclaim 16, wherein as a methylated derivative of β-cyclodextrin, RAMEB orTRIMEB is used.
 18. Process according to claim 15, wherein the twocomplex components are dissolved in the same or different solvent(s),preferably aqueous solvents, and then are combined, or wherein one ofthe components is dissolved, and the other is added in solid form tothis solution.
 19. Process for the production of a complex according toclaim 1, wherein a) the methylated derivative of β-cyclodextrin and thevitamin D compound are added together in soluble form, b) are stirredfor 1-24 hours, c) the optionally obtained solid is filtered off andoptionally dried, d) the complex is obtained from the filtrate (=afterthe solution that is separated from the solid is filtered) byconcentration by evaporation of the filtrate, freeze-drying,spray-drying or vacuum-drying.
 20. Pharmaceutical composition thatcontains a complex according to claim
 1. 21. Pharmaceutical compositionaccording to claim 20, in addition containing galenical adjuvants and/orvehicles.
 22. Pharmaceutical composition according to claim 20, wherebyan administration unit contains 0.1 μg to 1000 μg, preferably 1.0 μg to500 μg, of the vitamin D compound or the vitamin D analog.
 23. Use of acomplex according to claim 1 for the production of a pharmaceuticalcomposition, whereby optionally the complex is mixed with one or moregalenical adjuvants and/or vehicle(s) and is administered in adispensing form to the administration units.
 24. Use according to claim23, whereby the pharmaceutical composition for prophylaxis and/ortreatment of a disease is prepared from the group that consists of“diseases that are characterized by hyperproliferation and deficientcell differentiation, in particular hyperproliferative diseases of theskin, such as psoriasis, pituriasis subia pilasis, acne, ichthyosis;pruritus; tumor diseases and precancerous diseases, such as intestinaltumors, breast cancer, lung tumors, prostate cancer, leukemia, T-celllymphoma, melanoma, beta cell carcinoma, squamous carcinoma, actinickeratoses, cervical dysplasias, metastasizing tumors of any type;diseases that are characterized by disruption of the equilibrium of theimmune system, in particular eczemas and diseases of the atopic group;and inflammatory diseases, such as rheumatoid arthritis, respiratorydiseases such as asthma; autoimmune diseases such as multiple sclerosis,diabetes mellitus type I, myasthenia gravis, lupus erythematosus,sclerodermia; bullous skin diseases such as pemphigus, pemphigoid,rejection reactions in the case of autologous, allogenic or xenogenictransplants as well as AIDS.”
 25. Use of a complex according to claim 1,or a pharmaceutical composition, for prophylaxis or treatment of adisease, whereby one or more administration unit(s) of thepharmaceutical composition is dispensed to an individual who is likelyto come down with the disease or who is suffering from it.